In the case of thrombosis, blood circulation failure is caused by the thrombus formed in the inside of an artery or a vein by one or more of platelet hyperaggregation, hypercoagulability by activation of the blood coagulation factor, and reduced thrombolytic ability. The resulting ischemia leads to reduction of oxygen and nutrients in the peripheral tissues including brain, heart, and other organs, and this mechanism is strongly related to the onset of diseases such as cerebral infarction and myocardial infarction which may result in fatal symptoms. Therefore, treatment of thrombosis is viewed as an important remedy in these diseases.
Various drugs are currently used for the treatment of thrombosis. Exemplary such drugs include antiplatelets which suppress platelet aggregation such as aspirin, ticlopidine, eicosapentaenoic acid (EPA), dipyridamole, and dilazep hydrochloride, and anticoagulants which suppress blood coagulation factor such as warfarin, heparin, low molecular weight heparin, and argatroban. These drugs are used either alone of in combination of two or more.
An antiplatelets such as aspirin suppresses formation of thrombus and clot at the impaired site of the blood vessel by suppressing development of the blood coagulation triggered by platelet aggregation by suppressing the formation of the aggregants. However, since platelets also bear the function of preventing hemorrhage from the blood vessel, excessive suppression of the platelet invites loss of physiological prevention of hemorrhage, and antiplatelet administration of the level sufficient for treating the thrombosis often causes difficulties.
In addition, since an antiplatelet such as aspirin does not exhibit direct anticoagulant action, it is often difficult to realize sufficient antithrombotic action solely by the antiplatelet in the patient suffering from the thrombosis.
Aspirin is also known to cause aspirin dilemma when it is administered at a high dose. More specifically, aspirin is known to induce a serious gastrointestinal dysfunction since physiological production of the substance protecting gastrointestinal mucosa is suppressed, and also, a dysfunction of blood circulation system since physiological production of vasodilator is suppressed. Accordingly, an escalation of the aspirin dose is not recommended. Administration of aspirin at a dose sufficient for the thrombosis treatment is also difficult in this respect.
In the meanwhile, administration of the anticoagulant at high dose is associated with the risk of side effects, and administration of the anticoagulant at a dose sufficient for the thrombosis treatment is also difficult.
Accordingly, combined administration of an antiplatelet such as aspirin at an adequate dose and an anticoagulant at an adequate dose is often useful in treating the thrombosis.
However, prevention of the thrombus formation is accomplished by an antiplatelet and an anticoagulant by different mechanisms, and bleeding tendency may become enhanced at a certain dose.
A new drug for treating thrombosis is disclosed in W098/11896, wherein an antithrombotic comprising a combination of HMG-CoA reductase inhibitor and aspirin is administered. HMG-CoA reductase inhibitor, which is known for its strong inhibitory action for HMG-CoA reductase, is used for reducing blood cholesterol. This drug, however, is not conceived as a therapeutic drug of thrombosis. In addition, W098/11896 does not specifically describe effects that would be achieved if HMG-CoA reductase inhibitor is administered by a combined administration, and the extent of the therapeutic effect remains unknown. Furthermore, there is no indication for the effects that would be achieved by the combined administration of a pitavastatin (U.S. Pat. No. 5,856,336, and Japanese Patent Application Laid Open No. 1-279866) which is a HMG-CoA reductase inhibitor with aspirin.